tbuckley/cabot-search huggingface dataset:
P591: EXPRESSION PATTERNS AND CLINICAL RELEVANCE OF IMMUNE CHECKPOINT RECEPTORS AND LIGANDS IN ACUTE MYELOID LEUKEMIA
Authors: Milan Jagurinoski, Rositsa Vladimirova, Maria Muhtarova, Milena Stojcov-Jagurinoska, Margarita Guenova
Journal: HemaSphere (2023)

Background: The immune system is a key factor in the pathogenesis and treatment of acute myeloid leukemias (AML). However, knowledge for the expression of checkpoint receptors and ligands is still scarce. Aims: The aim of the study is to investigate the expression patterns of immune checkpoints on major immune cell subtypes and the respective ligands on the leukemic population as well as the correlation with clinical outcomes. Methods: A total of 40 consecutive patients with AML (incl. 17 myelodysplasia-related, MR-AML, and 23 de novo) were included in the study: 26 males and 14 females with a mean age of 59.65±15.19 years. The expression of CD279 (PD-1); CD153 (CTLA-4), and CD366 (Tim-3) was evaluated on major lymphocytic subtypes, while the respective ligands as follows: CD273 (PD-L1), CD274 (PD-L2), CD80, CD86, and CD66a, were detected on the leukemic population by flow cytometry. Therapeutic response and survival were assessed. Results: Checkpoint ligands demonstrated a wide range of expression on leukemic cells. CD66a was found from 3.1% to 87.4%; CD273 and/or CD274 on 0.2-6.2%; and CD80 and/or CD86 on 0.8-71%. Heterogeneous patterns were observed in regard to checkpoint receptors on major lymphocytic subpopulations. MR-AML and de novo AML differed significantly in ligand expression, while receptors on lymphocyte populations showed no significant differences. Higher expression of CD66a was more common in MR-AML (70.6%) compared to de novo AML (21.7%)(p=0.006) while CD273/CD274 was significantly lower, 5.9% vs 21.7%, respectively (p=0.035). High expression of CD273±CD273 was associated with shorter overall survival (median 51.9 months vs 31.4 months, log rank test p=0.03). Certain patterns contributed further to unfavourable outcomes such as high CD152 on NK and/or T-cells with high CD80±CD86 on blast cells; high CD279 on NK and/or T-cells with high CD274±273. Summary/Conclusion: Expression patterns of immune checkpoint receptors and ligands in AML correlates with poor clinical outcome. Further studies are warranted to possibly design potential immune biomarkers for improved stratification and therapeutic strategies. Keywords: Tumor immunity, AML, CTLA-4
PB1919: MATURE B-CELL NEOPLASMS CD5 NEGATIVE: CONFRONTATION CYTOMETRY-CYTOLOGY
Authors: Hanen Ben Cheikh, Lina Mohamed, Wided Moatemri, Seif Ncibi, Kmira Zahra, Abderrahim Khelif, Nejia Braham Jmili
Journal: HemaSphere (2023)

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Lymphocyte immunophenotyping by flow cytometry (CMF) is the gold standard for the differential diagnosis of mature lymphoid neoplasms (MLN). Aims: Our work aimed to compare the cytometric data to the cytological aspect of lymphoid cells for the diagnosis of MLN type CD5 negative. Methods: This is a retrospective study carried out in the hematology laboratory of the hospital (Farhat Hached, Sousse, Tunisia), including all patients with hyperlymphocytosis during 2 months or more, and a CD19+ and CD5- phenotype over a period of 3 years, from January first, 2019 to December 31, 2021. Data analysis was carried out using SPSS 21 software. Results: Out of 120 patients for whom immunophenotyping by CMF (Panel: CD19, CD5, CD23, FMC7, CD22, CD20, CD79b, CD10, CD103, CD43, CD38, CD25, CD11c, CD2, CD3, Kappa, Lambda) 16 patients had a CD19 + and CD5 – phenotype with a sex ratio (M/F) of 0.6. The median age was 63 years [36 – 74]. At the time of the analysis, 50% of patients had splenomegaly and/or lymphadenopathy and almost all patients had hyperlymphocytosis (mean: 23,904/mm3). Examination of the blood smear had revealed the presence of atypical lymphocytes in 12 patients (villous lymphocytes: 4 cases, hairy cells: 2 cases, prolymphocytes: 1 case, lymphocytes reminiscent of follicular lymphoma or mantle cell lymphoma: 2 cases, lymphocytes with cytoplasm extended hyperbasophilic or without specificity: 4 cases). The phenotypic profile: was in favor of marginal zone lymphoma (MZL) in 57.14%, characteristic of hairy cell leukemia in two patients characterized by CD103, CD11c and CD25 positivity and was compatible with prolymphocytic leukemia in one patient. Summary/Conclusion: Although the diagnosis was established for the majority of patients, additional examinations such as molecular biology were necessary for others such as follicular lymphoma and marginal zone lymphoma which were suspected but not confirmed. Keywords: Lymphoproliferative disorder, Cytometry, B cell lymphoma
PB1951: PROGNOSTIC SIGNIFICANCE OF CLINICAL INDICATORS RELATED TO AMINO ACID METABOLISM IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Ming Liu, Lili Feng, Peipei LI, Kang Lu, Yujie Jiang, Ya Zhang, Xin Wag
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, with a highly variable clinical course, which makes the study of prognostic influences and treatment options for CLL patients particularly important. Cancer cells readjust their metabolic pathways to accommodate their nutritional demands for reducing equivalents, increased energy and cellular biosynthesis. Altered amino acid metabolism is one way to achieve these demands. Amino acid metabolism plays an important role in the development and progression of CLL. However, there is still a lack of clinical biochemical indicators associated to amino acid metabolism to evaluate the prognosis of CLL patients. Aims: The study aimed to investigate the impact of clinical indicators related to amino acid metabolism on the prognosis of CLL patients and to develop a novel amino acid metabolism scoring system to optimize the risk assessment of CLL patients. Methods: CLL patients who were treated in Shandong Provincial Hospital between October 2010 to April 2022 were assessed from the Shandong Provincial Hospital CLL (SPHCLL) database. The univariate Cox regression analysis and multivariate Cox regression analysis were applied to evaluate the prognostic values of clinical indicators related to amino acid metabolism. Survival curves were constructed using the Kaplan-Meier method. The prognostic capacities of the novel scoring system were measured by areas under the curve (AUCs) of receiver operating characteristic curves. Results: A total of 634 CLL patients were randomly assigned to the training set (n=432) and validation set (n=202). Independent prognostic significance of hemoglobin (Hb, p=0.004), cystatin (Cys, p=0.018) and glutamyl transpeptidase (GGT, p=0.006) was determined in the training set by univariate and multivariate Cox regression analysis. The clinical indicators related to amino acid metabolism, Hb, CysC and GGT, were selected for establishing a novel amino acid metabolism score system (AAMS) model in CLL patients: AAMS= -1.082*Hb+0.862*CysC+0.842*GGT. CLL patients in the training set were divided into low and high subgroups based on the median AAMS. AAMS had independent prognostic significance in the prognosis of CLL patients (p=0.017), and a higher AAMS indicates a poorer prognosis for CLL patients. AAMS (AUC=0.755) also showed better predictive performance compared with Binet stage (AUC=0.568) and Rai stage (AUC=0.592) in CLL patients of the training set. These conclusions are well proved in the validation set. Summary/Conclusion: AAMS was an independent prognostic factor for CLL patients.This study analyzed the prognostic effects of clinical indicators related to amino acid metabolism in patients with CLL and developed a new scoring system to optimize accurate risk assessment in CLL patients. Keywords: Chronic lymphocytic leukemia
P565: REAL-WORLD DATA AS SUPPLEMENTARY CONTROLS FOR THE PROSPECTIVE RANDOMIZED HOVON-103 TRIAL IN INTENSIVELY TREATED ELDERLY ACUTE MYELOID LEUKEMIA PATIENTS
Authors: Sjoerd Hermans, Yvette van Norden, Erik van Werkhoven, Avinash Dinmohamed, Peter Huijgens, Gert Ossenkoppele, Gerwin Huls, Bob Löwenberg, Thomas Pabst, Dimitri Breems, Douwe Postmus, Francesco Pignatti, Jurjen Versluis, Jan Cornelissen
Journal: HemaSphere (2023)

Background: To replace or supplement control patients in prospective phase II/III studies, it has been suggested to use Real-World Data (RWD). However, it is unknown how outcome of RWD patients compares to outcome of trial control patients. Aims: Here, we compared the outcome of control patients of the prospectively randomized phase II HOVON-103 (H103) trial for elderly, intensively treated AML patients with the outcome of similarly treated elderly AML patients registered by the Netherlands Cancer Registry (NCR). Methods: The H103 randomized 679 patients between standard first-line intensive chemotherapy with or without selinexor, tosedostat, or lenalidomide, in 3 consecutive randomizations. We retrospectively identified 2,469 newly diagnosed elderly AML patients between 2014-2018 from the NCR, of whom 322 were selected for comparison with all H103-controls (n=279) based on first-line intensive treatment, WHO performance score ≤2 or unknown WHO status, and time between diagnosis and treatment ≤33 days. We performed 1:1 nearest neighbor propensity score matching (PSM) for age, modified European LeukemiaNet (ELN) 2017 AML risk classification, and white blood cell count. Results: Before PSM, NCR-patients compared well with H103-controls for age (median: 69 vs. 69 years, P=0.51), sex (61.5% vs. 61.6% male, P=1.00), blood parameters, and modified ELN2017 risk classification (16.8% vs. 13.3% favorable, P=0.43). WHO performance status was missing in 53.7% of NCR-patients vs. 1.4% in H103-controls. Comorbidity and toxicity data were absent in the NCR. Patient characteristics were also balanced after matching. After PSM, the 2-year OS was 29±3% for NCR-patients vs. 39±3% for H103-controls (Figure 1). Summary/Conclusion: Selected NCR-patients were comparable with H103-controls for most patient characteristics present in both databases. However, a significantly lower OS was observed for NCR-patients. The lack of recorded performance status and absence of comorbidity and toxicity scores in NCR-patients might explain these differences. Unless RWD AML are supplemented with these important scores, RWD cannot fully replace phase II/III trial control patients.Keywords: Clinical trial, Real world data, Acute myeloid leukemia
S242: MAST CELLS ARE MEDIATORS OF INFLAMMATORY EFFECTOR CELL RECRUITMENT AND FIBROSIS IN DERMAL CHRONIC GRAFT-VERSUS-HOST DISEASE
Authors: Senthilnathan Palaniyandi, Gerhard Hildebrandt
Journal: HemaSphere (2023)

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for patients with blood cancers. Benefits of allo-HCT are hampered by graft-versus-host-disease (GVHD), which can be debilitating and potentially lethal. In chronic GVHD (cGVHD), inflammation and aberrant wound healing lead to pathological fibrosis, most frequently in the skin, yet the exact pathophysiology is not well-understood. Mast cells are an important part of the immune system and involved in atopic disease. Recent studies have demonstrated new paradigms for mast cell activity, showing that they also play an important role in wound healing and fibrosis. Aims: Our study is aimed to understand the role of mast cells as effectors of inflammatory effector cell recruitment and fibrosis in dermal cGVHD after allo-HSCT Methods: In a murine model of cGVHD (LPj into C57BL/6), lethally irradiated wild type (wt) mice and mast cell-deficient (mcd) B6.Cg-KitW-sh recipients received bone marrow and T cells from either syngeneic wt B6 or allogeneic LP/J donors. Animals were monitored until day 50 after allo-HCT and analyzed for chronic GVHD related organ injury and associated inflammatory and fibrotic changes. Results: Allogeneic wt recipients had significantly more cGVHD symptoms than mast cell-mcd B6.Cg-KitW-sh recipients. Clinical GVHD scores correlated with a significant increase in skin pathology (dermal thickness and sclerosis), collagen deposition, and expression of pro-fibrotic genes in WT as compared to mcd mice. Dermal mast cell numbers were increased in wt recipient mice, but were nearly undetectable in mcd recipient mice, implying that the mast cells that are present were recipient-derived and had survived conditioning. Skin from allogeneic wt but not mcd recipients was enriched in T cells and cytokines (IL-33, IFNgamma, TNF alpha, IL-1b, IL-6, IL-21) as well as chemokines (CCL2, CCL4, CCL5, CXCL5, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16). This increase associated with expression of ST2, IL-21R, CXCR3 and CXCR6, MMP12, ICOS. mRNA expression for CD80, CD86 lymphocyte activation score was also increased. Supernatant from stimulated mast cells induced fibroblast proliferation in vitro. Mast cells upon stimulation with IL33 were sources of many of these factors, production of which was blocked when treated with ibrutinib and ruxolitinib. Summary/Conclusion Recipient mast cells contribute to a proinflammatory environment in the skin after allogeneic HCT, leading to T cell recruitment and progressive fibrosis. Mast cell function or dependent pathways present novel targets to prevent and treat this devastating complication of allo HCT. Keywords: Chronic graft-versus-host, Mast cell, Allogeneic hematopoietic stem cell transplant, Mouse model
P1640: REAL-WORLD SUPPORTIVE EVIDENCE FOR THE 4D-DVT ALGORITHM: ADJUSTING D-DIMER THRESHOLDS FOR INITIAL AND FOLLOW-UP IMAGING OF PATIENTS WITH SUSPECTED DEEP VEIN THROMBOSIS BY CLINICAL PROBABILITY
Authors: John Willan, Gaurav Agarwal, Tara Varghese, Karen Cairns, Peter Baker, Nicola Curry
Journal: HemaSphere (2023)

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Patients presenting with suspected deep vein thrombosis (DVT) are risk-stratified by the Wells’ score and plasma D-dimer. However, whilst the majority of patients require imaging, only a small minority are diagnosed with DVT. Kearon and colleagues1 have proposed an updated algorithm, using different D-dimer thresholds for the initial and follow-up scan adjusted according to the initial Wells’ score, to determine the need for first or second scans. Aims: We aimed to assess the performance of this novel algorithm, by retrospectively applying it to a large, single-centre, retrospective cohort. We aimed to establish the rates of DVTs that would have been missed, and the reduction in ultrasound scans required per patient. Methods: We reviewed clinical records of 12,365 presentations of suspected DVT to our specialist clinic, from 1st January 2012 to 31st July 2022, for whom a complete Wells’ score and D-dimer were available. Results: Of 12,365 presentations, there were 1,315 DVT diagnoses. A further 20 patients were diagnosed at re-presentation within 90 days [0.2% rate of missed DVTs (95% confidence interval 0.20-0.20%)]. In this cohort, the modified algorithm (Figure 1) would have detected 1,268 DVT cases, missing 47 patients (and also the 20 patients who re-presented). This is a 0.61% rate of missed DVTs (95% confidence interval 0.61-0.62%). The conventional algorithm would lead to 19,277 ultrasound scans [mean of 1.56 (95% confidence interval 1.55-1.57) scans per patient]. In comparison, the modified algorithm would lead to 11,248 ultrasound scans [mean of 0.91 (95% confidence interval 0.90-0.92) scans per patient]. Taken together, the modified algorithm reduces number of scans by 42%, missing one DVT diagnosis for every 171 scans saved compared to the conventional approach.Summary/Conclusion: The modified algorithm can detect the vast majority of DVTs and maintain a low rate of missed DVTs, whilst very significantly reducing the number of ultrasounds required. This could save resources for healthcare systems, and travel time and uncertainty for patients. 1 – Diagnosis of deep vein thrombosis with D-dimer adjusted to clinical probability: prospective diagnostic management study. Kearon C., et al. BMJ 2022;376:e067378 Keywords: Deep venous thrombosis, Diagnosis
P952: PROGNOSTIC SIGNIFICANCE OF DYNAMIC CHANGE OF MAGE-C1/CT7 IN MULTIPLE MYELOMA: TEN YEAR EXPERIENCE FROM A SINGLE CENTER
Authors: Xuelin Dou, Fengrong Wang, Huan Chen, Yao Chen, Lei Wen, Yang Liu, Shasha Wang, Wenbing Duan, Guorui Ruan, Xiaosu Zhao, Kaiyan Liu, Xiaojun Huang, Jin Lu
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The prognostic role of bone marrow (BM) minimal residual disease (MRD) such as next-generation flow (NGF) and next-generation sequencing (NGS) had been widely validated, requiring specific platform and facility. Previous study shows MAGE-C1/CT7 correlated with clinical parameters at diagnosis of MM. The quantitation of the BM expression level of MAGE-C1/CT7 is economical and easy to operate. Aims: We aim to answer the question that whether the dynamic change MAGE-C1/CT7 could serve as a candidate for MRD detection in MM. Methods: Clinical records of patients diagnosed with multiple myeloma receiving novel agents’ induction and then underwent ASCT from March 2011 to November 2021 at Peking University People’s Hospital were retrospectively collected. Patients without MAGE-C1/CT7 expression level in the bone marrow (BM) ever tested were exclued from the study. Results: Two-hundred and fifteen multiple myeloma patients receiving novel agents’ induction as well as ASCT as frontline therapy, with BM MAGE-C1/CT7 levels longitudinally monitored were included in the analysis. The positive rate of MAGE-C1/CT7 at baseline was 87.2% with a median level of 4.46 (0.01-939.5) %. Patients presented with BMPC < 10% and EMD were lesser in MAGE-C1/CT7 positive than negative group. In univariate Cox regression analysis, peri-ASCT MAGE-C1/CT7 status showed better discriminatory ability of PFS and OS than peri-ASCT MRD status assessed by flow cytometry (Figure). In multivariate analysis, both peri-ASCT MAGE-C1/CT7 status and R2-ISS staging predicted PFS independently. We also found that a 2-log decrease of MAGE-C1/CT7 post-induction cycle 2 compared to baseline correlated with peri-ASCT MAGE-C1/CT7-- status.Summary/Conclusion: Our data showed the independent predictive value of peri-ASCT MAGE-C1/CT7 status on PFS in MM patients receiving novel agents and ASCT as frontline treatment. A 2-log decrease of MAGE-C1/CT7 post-induction cycle 2 correlated with peri-ASCT MAGE-C1/CT7-- status, which provided an earlier prognostic marker during treatment. Keywords: Gene expression, Multiple myeloma, Autograft
L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab
Authors: Ilaria Marrocco, Suvendu Giri, Arturo Simoni-Nieves, Nitin Gupta, Anna Rudnitsky, Yuya Haga, Donatella Romaniello, Arunachalam Sekar, Mirie Zerbib, Roni Oren, Moshit Lindzen, Damon Fard, Yasuo Tsutsumi, Mattia Lauriola, Luca Tamagnone, Yosef Yarden
Journal: Cell Reports Medicine (2023)

EGFR-specific tyrosine kinase inhibitors (TKIs), especially osimertinib, have changed lung cancer therapy, but secondary mutations confer drug resistance. Because other EGFR mutations promote dimerization-independent active conformations but L858R strictly depends on receptor dimerization, we herein evaluate the therapeutic potential of dimerization-inhibitory monoclonal antibodies (mAbs), including cetuximab. This mAb reduces viability of cells expressing L858R-EGFR and blocks the FOXM1-aurora survival pathway, but other mutants show no responses. Unlike TKI-treated patient-derived xenografts, which relapse post osimertinib treatment, cetuximab completely prevents relapses of L858R+ tumors. We report that osimertinib's inferiority associates with induction of mutagenic reactive oxygen species, whereas cetuximab's superiority is due to downregulation of adaptive survival pathways (e.g., HER2) and avoidance of mutation-prone mechanisms that engage AXL, RAD18, and the proliferating cell nuclear antigen. These results identify L858R as a predictive biomarker, which may pave the way for relapse-free mAb monotherapy relevant to a large fraction of patients with lung cancer.
Implications of Nonhuman “Authors”—Reply
Authors: Annette Flanagin, Kirsten Bibbins-Domingo
Journal: JAMA (2023)

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Review of Prediabetes—Reply
Authors: Sam Dagogo-Jack
Journal: JAMA (2023)

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